Process for the epimerization of 11-keto 5alpha, 9alpha, 10alpha-steroids to the corresponding 11-keto-5alpha, 9beta, 10alpha-steroids



United States Patent No Drawing. Fiied Jan. 10, 1963, Ser. No. 250,479 Claims priority, application Mexico, ()ct. 11, 1962,

Claims. (31. 260 397.4s

The present invention relates to a novel method for the production of cyclopentanophenanthrene derivatives.

More particularly the present invention relates to a novel process for the production of 5a,9}3,l0a-St610ld5, especially those belonging to the estrane (l9-nor-androstane)and l9-nor pregnane series.

The 5ot,9/3,10u-configuration has a striking effect on the physiological properties of steroids. For example, in the estrane series, 5u,9fi,l0a-estrane-3,l1,17-triol is a very active anabolic agent and is a sedative of the central nervous system; 19 nor-5419B,lOu.-pregnan-l7aol-3,1l,- 20-trione and similar compounds, are powerful progesta tional agents, with good oral activity and very useful incontrolof fertility, likewise, they reduce the cholesterol level in the blood.

In addition to theaforementioned properties, the ,9B; l0a-steroids, object of the present invention, are intermediate compounds in the production of retro-steroids (95,100!) of importance known to those skilled in the art. Starting with the compounds of the present'invention there may be prepared, for example, 19-nor-9B,10or-progesterone, l9-nor-9;3,10ct-testosterone and similar compounds, by conventional methods.

In accordance with the present invention the surprising discovery has been made that the 11-keto-5a,10a-steroids, obtained by catalytic hydrogenation of A A2500) -or M -steroids, having a hydroxyl or keto group at C-ll followed by conventional oxidation in order to transform the oxygen bearing groups at C-ll' to keto groups, by treatment in an alkaline medium, produce the corresponding l1-keto-5a,9;3,Illa-steroids, which may be treated by conventional means to. give the respective ll-desoxy derivatives, the respective 1 10: or llfi-hydroxyl derivatives or similar compounds.

The novel process of the present invention is represented by the following scheme:

3,234,244 ?atented Feb. 8, 1966 ice In the above formulae wherein only the rings, A, B, and C of the steroid nucleus are represented, R represents hydrogen or a lower alkyl group; R represents hydrogen or a lower alkyl group; R represents a lower alkyl group; X and Y, each represents a hydroxyl group in position on or B or a keto group; Z represents a hydroxyl group, a lower alkoxy group or a keto group and the 5 indicates that the substituent attached thereby to the steriod nucleus may be in positions a or {3.

The starting compounds of the process outlined above (I, II, III) belong preferably to the estrane (l9-norandrostane) and 19-nor-pregnane series and are A triene, A -diene or A -ene derivatives with a hydroxyl or keto group at C1l and preferably with a keto group, a lower alkoxy or hydroxy at (1-3. In the steroid molecule, there may be present several substituents without interfering with the normal course of the reaction of the present process. For example, lower alkyl groups may be present in positions Cl,.C-2, C-4, C-6,.Cl2, Cl5, C-16 and/ or C-17; hydroxyl groups or keto group may be present in positions C6, C7, (3-12, 0-15, 0-16 and/ or C-17. There may also be present in the molecule, derivatives of the foregoing functional groups which are usual in steroid chemistry and are known to those skilled in the art, such as acyloxy, alkoxy, formyl groups, and the like.

By proceeding in accordance with the above scheme, a starting compound of the type mentioned hereinbefore (I, II, or III) is hydrogenated under a pressure of approximately 1 to atmospheres, at a temperature between approximately 80 and C. during a period of time of the order of 5 to 30 hours, in an organic solvent, preferably polar, such as a lower hydrocarbon alcohol, for ex ample ethanol, or a lower alkyl ester of a hydrocarbon carboxylic acid of up to 8 carbon atoms, such as for example, ethyl acetate, in the presence of aheavy metal catalyst, preferably pertaining to the group of transitional elements of the Periodic Table, such as platinum, ruthenium, palladium or nickel, and optionally in the presence of an acid, if there is no 3-alkoxy-A -grouping present, preferably mineral, such as hydrochloric acid, or of a base, if there is no 3-keto-A -moiety present, preferably a hydroxide or a lower alkoxide of an alkali'metal, such as sodium hydroxide or sodium methoxide, thus giving the corresponding 11 hydroxy 5a,l0ocsteroid (IV:Y=hydroxy). The ll-hydroxy group of the latter steroid, which may have its origin in the hydroxyl group existing in the starting compound or in the reduction of a keto group in the course of the catalytic hydrogenation,

is oxidized by conventional methods, for example using chromium trioxide in acid solutions or pyridine solutions, thus furnishing the corresponding ll-keto derivatives (W:Y=keto). These ll-keto'-5u,10a-steroids are treated with a base, preferably an alkali metal hydroxide or lower alkoxide, such as sodium hydroxide or sodium methoxide, in an organic solvent preferably polar, such as a lower hydrocarbon alcohol, e.g; methanol, during approximately 1 to 24 hours and at a temperaturebetween room and steam bath temperatures, thus affording the corresponding 1l-keto-5u,9fi,l0a-steroids (V).

3 "The 1l-keto-5a,95,low-steroids, obtained by the above described procedure may undergo a series of conventional transformations, such 'as the reduction of the keto group to hydroxy group, or the total'eliminat-ion thereof, e.g. by treatment according to the Wolff-Kishner reaction, without losing the 5 a,9B,10a-configuration.

The isolation, of the reaction products of the present process has no critical importance and may be effected according to conventional methods, it being also possible for the products of a reaction in the form of a solution to be treated by the subsequent reaction method, thus undergoing the same transformations as if it were isolated and in solid form.

Examples of compounds which may be prepared by the process of the present invention are:

3-rnethoxy-l fi-methyl5a,9,6', lOa-estrane-l 1,17-dione.

3[3-methoxy-l9-nor-5a,9fi, lOa-pregnan-17a-ol-1 1,20

dione.

3,8-methoxy-1fl-methyl-19-nor-5a,9(3,lOa-pregnane-11,20-

dione.

3 fi-rnethoxy-l ocI116thyl-5oc,9[3, 1 Oa-estrane-l 1,17-dione.

3 3-methoxy-1a-methyl-19-nor-5u,9[3,IOa-pregnane-11,20-

dione.

1u-methyl-5or,95, 10a-estrane-3, 11,17-trione.

19-nor-5 rx,9 [3,10a-pregnane-3 ,11,20-trione.

19-nor-5 (1,9,6, 10a-pregnan-17a-ol-3 ,11,20-trione.

1a-methyl-19-nor-5u,9f3,10a-pregnane-3,l 1,20-trione.

1/3-methyl-19-nor-5a,9fi, 1 a-pregnane-3, 1 1,20-trione.

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention:

PREPARATION 1 To a suspension of 25 g. of estrone cycloethyleneketal in 25 cc. of acetone there was added a solution of 70 g. of potassium hydroxide in 37.5 cc. of water and the stirred mixture was treated dropwise with 40 cc. of methyl sulfate. The reaction mixture was then stirred for 45 minutes further, poured into dilute hydrochloric acid solution and the formed precipitate collected by filtration. Crystallization from chloroform-methanol gave the 3- me thyl-ether 17-cycloethyleneketal of estrone.

, A solution of 10 g. of the 3-methy1 ether l7-cycloethyleneketal of estrone in 200 cc. of anhydrous dioxane was refluxed during 24 hours with 1.1 molar equivalents of 2,3-dichioro-5,6-dicyano-1,4-benzoquinone. It was then cooled, the hydroquinone formed during reaction was separated by filtration and the filtrate was diluted with 1 liter of ethyl acetate. The resulting solution was washed with 1 liter of a 1% aqueous solution of sodium hydroxide, with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.

The crystalline residue was dissolved in 200 cc. of acetone and the resulting solution was passed through a column of 400 g. of alumina. The less polar crystalline fractions were combined and recrystallized from methylene chlorine hexane to give the 3-methyl ether 17-cycloethyleneketal of the A -dehydro-estrone.

Through a solution of 10 g. of the 3-rnethyl ether 17- cycloethyleneketal of A -dehydro-estrone in 300 cc. of anhydrous tetrahydrofurane, was passed a current of diborane during 3 hours and the reaction mixture was kept at room temperature overnight under anhydrous conditions. The excess of diborane was decomposed with water, the solution extracted with methylene chloride and the organic extract washed with water to neutral, dried over sodium sulfate and evaporated to dryness. The oily residue was dissolved in 45 cc. of acetone and 225 cc. of ethanol, was cooled to C. and there were added, dropwise, 650 mg. of sodium hydroxide dissolved in 6 cs.

PREPARATION 2 Estradiol was treated according to the techniques de-' scribed in Preparation 1, producing successively the 3-- methyl ether of estradiol, the 3-methyl ether of A dehydro-estradiol and the 3-methyl ether of lla-hydroxyestradiol.

PREPARATION 3 l-methyl-estrone was conventionally converted into the corresponding cycloethyleneketal and then was treated following the techniques described in Preparation 1, giving successively the 3-methyl-ether-l7rcycloethyleneketal of l-methyl estrone, the 3-methyl-ether-l7-cycloethyleneketal of l-methyl-A -dehydro-estrone, the B-methylether-17-cycloethyleneketal of l-methyl-lla-hydroxy-estrone, and the S-methyl-ether of l-methyl-llu-hydroxyestrone.

PREPARATION 4 l-methyl-estradiol was treated in accordance to Preparation 1, thus being obtained successively the S-methylether of l-methyl estradiol, the 3-methyl-ether of l-methyl-A -dehydro-estradiol and the 3-methyl-ether of 1- methyl- 1 lot-hydroxy-estradiol.

PREPARATION 5 19-nor-A -pregnatrien-3-ol-20-one was treated fol lowing the techniques described in Preparation 1, giving successively 3 methoxy-19 nor-A -pregnatrien-20- one, 3 methoxy 19-nor-A -pregnatetraen-20- one and S-methoxy-19-nor-A -pregnatriene-lloc,20fidiol.

PREPARATION 6 l9 nor A -pregnatrien-3,l7a-diol-2O-one was treated in accordance with Preparation 1, thus producing successively 3-methoxy-l9-nor-A -pregnatrien-17mol-20-one, 3-methoxy-19-norA -pregnatetraen- 17ot-ol20-one, and 3-methoxy-19-nor-A -pregnatrien-l 10c,17oz,20{3-1Ii01.

PREPARATION 7 1 methyl-19-nor-A -pregnatrien-3-ol-20-one was treated following the methods described inPreparation l to give successively 3-rnethoxy-l-methyl-l9-nor-A pregnatrien-20-one, 3-methoxy-1-methyl-19-nor-A -pregnatetraen-20-one and 3-methoxy-1-methyl-l9- nor-A -pregnatriene-l 10:,205-di0l.

PREPARATION 8 A cold solution of 6 g. of 3-methy1 ether of lla-hy droxy-estrone in 750 cc. of anhydrous ether was added to 900 cc. of liquid ammonia followed by 7.8 g. of lithium in small pieces over a period of 10 minutes with constant stirring. The mixture was stirred during 20 minutes more, then there were cautiously added cc. of absolute ethanol and the ammonia'was evaporated. Water was added to the residue, the ether distilled off and 3-methoxy- A -estradiene-llu,17/3-diol was obtained.

Following the same procedure the compounds set forth under A were converted into the respective products listed under B.

3-methyl-ether i l-methyl-llahydroxy-estrone. 3-methoxy-19nor-A 13 -pregnatrien-11a-ol-20one. 3-methoxy-19-n0r-A pregnat-l'lene-lloz,lToHliOl-QCLOHB. 3-methoxy-l-methyl-lQ-nor-A -pregnatrien-lla-ol--one.

PREPARATION 9 PREPARATION 10 A solution of 10 g. of estrone cycloethyleneketal in 200 cc. of anhydrous dioxane was refluxed during 24 hours with 1.1 molar equivalents of 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone. It was then cooled, the hydroquinone formed during reaction was separated by filtration and the filtrate was diluted with 1 liter of ethyl acetate. The resulting solution was washed with 1 liter of a 1% aqueous solution of sodium hydroxide, with water to neutral dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.

The crystalline residue was dissolved in 200 cc. of acetone and the resulting solution was passed through a column of 400 g. of alumina. The less polar crystalline fractions were combined and recrystallized from methylene chlorine-hexane to give the A -dehydro estronecycloethyleneketal.

Through a solution of 10 g. of the latter M -dehydroestrone ketal in 300 cc. of anhydrous tetrahydrofurane, was passed a current of 'diborane during 3 hours and the reaction mixture was kept at room temperature overnight under anhydrous conditions. The excess of dioorane was decomposed with water, the solution extracted with met. ylene chloride and the organic extract washed with water to neutral, dried over sodium sulfate and evaporated to dryness. The oily residue was dissolved in cc. of acetone and 225 cc. of ethanol, was cooled to 5 C. and there were added, dropwise, 650 mg. of sodium hydroxide dissolved in 6 cc. of water and cc. of 35% hydrogen peroxide. The mixture was stirred during 1 hour, neutralized with acetic acid and extracted with methylene chloride. The organic extract was Washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was chromatographed on 400 g. of washed alumina. By crystallization of the solid fractions there was obtained lla-hydroxy-estrone cycloethyleneketal.

The latter compound was treated with 1 cc. of concentrated hydrochloric acid in 250 cc. of acetone. Upon conventional isolation there was produced lloc-hYdrOXY- ESU'QHB.

Following exactly the same techniques there were treated the compounds set forth under A, thus being ob- 6 tained as final products the cor-responding compounds listed under B:

Estradiol lla-hydroxyestradicl. latneltthyl-estrone cycloethylenekel-methyl-lla-hydroxy-estrone.

a. 1-methyl-estradiol l-methyl-l'la-hydroxy-estmdiol, 19-nor-A -pregnatrien-Zl-ol- 19-nor-A -pregnatriene-3, 11,

20-0ne. 20fi-trio1. 19-nor A -pregnatrine-E, 17a- 19-nor-A -pregnat-riene Q-I 1a,

diol 2O-0ne. 17a,2ofi-tetrol.

' 1-1'nethyl-19-nor-A pregnar trien-3-ol-2D one.

triene-3,11u,20B-triol.

Example I A solution of 10 g. of 3-rnethyl-ether of llu-hydroxycstrone in cc. of ethanol and 1 cc. of a 40% aqueous solution of sodium hydroxide, was mixed. with 2 g. of ruthenium oxide and treated with hydrogen under a pressure of atmospheres at 175 C. during 12 hours. The catalyst was filtered off and the filtrate neutralized with acetic acid and evaporated to dryness. The residue was chromatographed on a column containing 400 g. of alumina, thus being obtained Sfi-methoXy-Sa,lOot-eStrane- 110:, l 7fl-diol.

Example 11 Example I was repeated except that the sodium hydroxide, solution was substituted by concentrated hydrochloric acid, thus being obtained the same compound as in said example.

Example 111 A solution of 2 g. of lla-hydroxy-estrone in 100 cc. of ethanol was stirred with 400 mg. of platinum oxide catalyst under hydrogen atmosphere at 150 C. under a pressure of 1 00 atmospheres during 5 hours. The catalyst was filtered oil and the filtrate neutralized with sodium bicarbonate solution. The resulting mixture was poured into water and the prdouct extracted with ethyl acetate; The organic extract was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was chromatographed on 80 g; of alumina, thus pIOduCiflg-5oc,1Qrzestrane-3,8,l1a,17;9-triol.

Example IV The 3-methyl-ether of lla-hydroxy-est rone was treated according to Example I, except that ruthenium oxide was substituted by 10% palladium on charcoal, thus giving 35-methoxy-5a,ltlmestrane-l1a,l7,8-di'ol.

Example V A solution of 10 g. of llu-hydroxyestradiol in 400 cc. of methanol was mixed with 2 g. of ruthenium oxide and treated with hydrogen under a pressure of 3 atmospheres at C. during 24 hours. The catalyst. was separated by filtration and the filtrate evaporated to dryness. The residue was chromatographed on 400 g. of alumina, to produce 5u,10a-estrane-3fl,1 1u,17fl-triol.

Example VI The technique described in Example V was. repeated, with the exception that ruthenium oxide was substituted by Raney nickel thus being obtained identical results to those of said example.

Example VII A solution of 2 g. of llu-hydroxy-estradiol in cc. of methanol was unixed with 2 g. of ruthenium oxide and treated with hydrogen under atmospheric pressure at 90 C. during 30 hours. The catalyst was filtered off and the filtrate evaporated to dryness. The residue was chromatographed on a column of 80 lg. of alumina, thus being obtained 5 a,10u-estrane-3,B,1 106,17fi-tl'l0l.

7 Example VIII A solution of 1 g. of 3B-methoxy-5oz,IOa-estrane- 11u,17(3-diolin-10'cc. of-acetone, was cooled to C., then treated under a nitrogen atomsphere and with stirring, with a solution of 8 N chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 cc. of concentrated sulfuric acid and diluting with water to 100 cc.), until the color of the reagent persisted in the mixture. It was stirred for 5 minutes further at 0-5 C. and diluted with water. The precipitate was collected, washed with water and dried under vacuum, thus affording a crude product which upon recrystallization from acetone-hexane gave 3fi-drnethoxy-5a,lua-estrane-l1,17- dione.

Example IX A solution of '6 g. of 3 fi-methQXy-SaJOa-estrane- 110:,17fi-di01 in 120 cc. of pyridine was added to a mixture of 6 :g. of chromic trioxide in 120 cc. of pyridine. The reaction mixture was kept at room temperature overnight. It was then diluted with ethyl acetate, filtered through Celite and the filtrate washed well with water, dried and evaporated to dryness. Crystallization from acetone-hexane afiorded 3 B-methoxy-S a,10a-estrane-1 1,17-

dione.

Example X A solution of 3 g. of 3 fl-methoxy-S a,10oe-estrane- 11,17-dione in 200 cc. of methanol was treated with 1 g. of sodium methoxide and the resulting solution was maintained at steam bath temperature for 1 hour, then it was poured into Water and the product extracted with methylene chloride. The organic extract was washed with dilute hydrochloric acid then with water, dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization of the residue from ethyl-acetate-hexane produced 3 8-methoxy-5a,9p, IOa-eStrane-I 1-17-dione.

Example XI A mixture of 5 g. of 3 fi-methoxy-S a,lOa-estrane- 11,17-dione and 100 cc. of 1% solution of potassium hydroxide in methanol was kept at room temperature for 24 hours.

Water was added and the whole was extracted with methylene chloride, the organic extract washed with water to neutral, dried and evaporated to dryness. Crystallization of the residue from acetone-hexane produced 38- methoxy-5a,9 8, IOa-estranel 1,17-dione.

Example XII The foregoing example was repeated except that potassium hydroxide was substituted by sodium hydroxide, thus being obtained identical results to those of said example.

Example XIII Example XIV The compounds listed under A were hydrogenated following the procedure described in Example III thus producing the respective products set forth under B.

3-methyl ether of lla-hydroxyestradiol.

S-methyl-ether of l-methyl-llahydroxy-estrone.

3-methyl-ether of l-methyl-llahydroxy-estradiol.

3-111ethoxy-lQ-nor-A -pregnatriene-llaflOB-diol.

B-methoxy-l-methyl-19-n0r- A J -pregnatrieue-11a,20fldiol.

l-methyl-lla-hydroxy-estradiolun BB-methoxy-Sa, 10a-estrane-11a,17;9

diol

ldmethyl-l il-nora,IOa-pregnane- 3B,11a,2018-triol.

Example XV The compounds named under A were oxidized following the procedure described in Example X111 thus being respectively obtainedthe products listed under B.

Sfl-methoxy-lB-methyl-M,10a-

estrane-11,17-dione. 3B-meth0xy-19-nor-5a,loot-pregname-11,20-dionc. 3fl-methoxy-l9-nor-5a,met-pregnan- 17a-o1-11,20 dione. 3fi-methoxy-1B-methyl-19-nor-5a,

10a-pregnane-1L20-dione. 3fi-methoxy-lwmethyl5a,10a-

estrane-11,17-dione. 3fl-methoxy-1a-methyl-19-nor-5a,

10a-pregnane-11,20-dioue. 5:2,100H3Si213116-3,11,17-tri0119. 1a-methyl-5a,10a-estraue-3,11,17-

trione. 19-nor-5a,10a-pregnane-3,11,20-

trione.

19-nor-5a,l0a-pregnane-17a-0l-3,11,

20-trione.

1a-methy1-19-nor-5a,mot-pregnanc- 3,11,20-trione.

lfl-methy1-5a,10a-estrane-3,11,17-

trione.

lB-methyl-19-n0r-5a,IOa-pregnane- 3,11,20-trionc.

Example XVI dione,

3 ,B-methoxy-l B-methyl-19-nor-5a,9,8,IOa-pregnane 11,20-dione,

3 /8-methoxy-1 a-methyI-S oc,9/3, IOa-estrane-I 1,17-dione, 3 B-methoxy-la-methyl-19-nor-5 0 9,8, IOa-pregnane- 11,20-dione,

511,95, 10a-estrane-3,1 1,17-trione, 1a-methyl-5a,9/3,10a-estrane-3 ,1 1, 17-trione, 19-nor-5u,9[3,10a-pregnane-3,11,20-trione, 19-I101'5oc,9,3, IOa-pregnan- 17a-ol-3,1 1,20-trione, 1amethyl-19-nor-5a,9;3,10a-pregnane-3 ,11,20-trione, 1/8-methyl-5a,9,8,10a-estrane-3 ,1 1,17-trione, 1,6-methyl-19-nor-5a,9,6,10a-pregnane-3,11,20-trione.

Example XVII The Example XI was repeated except that methanol was substituted by ethanol, thus being obtained results identical to those of said example.

9 Example XVIII Example XII was repeated except that ethanol was used instead of methanol, thus giving 3B-m6thOXy-5oa,9fi,l0uestrane-11,17-dione.

I claim:

1. A process for the preparation of a compound selected from the group consisting of a 3B-hydroxy-5m,913,10m-l1- ketoestrane, a 3B-lower alkoxy-a,9;3,l0a-1l-ketoestrane, a 3 3-hydroxy-5u,9;3,10a-1l-keto 19 norpregnane and a B s-lower alloxy-5oz,9B,l0a-11-keto-19-norpregnane which is otherwise unsubstituted in its A-ring and at positions 6, 8 and 9 except by hydrogen atoms which comprises treating the corresponding 9a-steroid with an alkaline medium.

2. Aprocess for the preparation of a compound selected from the group consisting of a 3fi-hyd1OXY-5u,9fi,10ozllketocstrane, a Bfi-lower alkoxy-5a,9fi,l0a-ll-ketoestrane, a 3 8-hydroxy-5m,9fi,l0a-ll-lceto- 19 norpregnane and a Sfi-lower alkoxy-5m,9;8,10a-11-keto-19-norpregnane which is otherwise unsubstituted in its A-ring and at positions 6, 8 and 9 except by hydrogen atoms which comprises treating the corresponding 9oc-Sl6l'0id, dissolved in a polar organic solvent, with a base selected from the group consisting of alkali metal hydroxide and alkali metal lower alkoxides.

3. A process for the preparation of a compound selected from the group consisting of a 3,t3-hydroxy-5a,9,6,10a-1lketoestrane, a 3f3-lower aIkoXy-SaSBJOa-l l-ketoestrane, a 3,8-hydroxy-Sa,9;3,10a-1l-keto 19 norpregnane and a 3fi-lower -alkoxy-5a,95,10a-11-keto-19-norpregnane which is otherwise unsubstituted in its A-ring and at positions 6, 8 and 9 except by hydrogen atoms which comprises treating the corresponding 9a-steroid, dissolved in a lower alkanol, with potassium hydroxide.

4. Atprocess for the preparation of a compound selected from the group consisting of a 3B-hydroxy-5u,9fi,10u-11 ketoestrane, a 3B-lower alkoxy-5a,9B,10a-1l-ketoestrane, a 3,6-hydroxy-5a,9,f3,10u-1l-keto 19 norpregnane and a 3,8-lower alkoxy-5a,9;3,10a-11-keto-19-norpregnane which is otherwise unsubstituted in its A-ring and at positions 6, 8 and 9 except by hydrogen atoms which comprises treating the corresponding 9a-steroid, dissolved in a lower alkanol, with sodium hydroxide.

5. A process for the preparation of a compound selected from the group consisting of a 3B-hydroxy-5a,9;3,10a-l1- ketoestrane, a 318-lower alkoxy-5a,9;8,10a-1l-ketoestrane, a 3,8-hydroxy-5ix,9;3,10a-1l-ke-to 19 norpre-gnane and a BB-lower alkoxy-5a,9}8,10a-11-keto-19-norpregnane which is otherwise unsubstituted in its A-ring and at positions 6, 8 and 9 except by hydrogen atoms which comprises treating the corresponding 9a-steroid, dissolved in a lower alkanol, with sodium methoxide.

6. A process for the preparation of a compound selected from the group consisting of a 3fi-hydroxy-5a,9fi,10a-11- ketoestrane, a 35-lower alkoxy-5a,9,8,10m-1l-ketoestrane, a 3fi-hydroxy-5a,9fl,l0a-ll-keto 19 norpregnane and a lip-lower alkoxy-51x,95,10a-1 1-keto-19-nor-pregnane which is otherwise unsubstituted in its A-ring and at positions 6, 8 and 9 except by hydrogen atoms which comprises treating the corresponding 9a-St61'0ld, dissolved in a lower alkanol, with sodium ethoxide.

7. A process for the preparation of a compound selected from the group consisting of a 3B-hydroxy-Sa,9,8,10a-11- ketoestrane, a Sit-lower alkoxy-5a,9,8,10a-1l-ketoestrane, a 3B-hydroxy-5a,9,8,10ul l-keto 19 norpregnane and a Zip-lower -alkoxy-5a,9;3,10 x-11-keto-19-norpregnane which is otherwise unsubstituted in its A-ring and at positions 6, 8 and 9 except by hydrogen atoms which comprises treating the corresponding S a-steroid, dissolved in methanol, with potassium hydroxide.

8. A process for the preparation of a compound selected from the group consisting of a 3B-hydroxy-5u,9fi,10a-11- ketoestrane, a 3B-lower alkoxy-5u,918,10a-1l-ketoestrane, a 3,8-hydroxy-5a,9B,10a-1l-keto 19 norpregnane and a L e-lower alkoxy-5rx,9;3,10a-11-keto-19-norpregnane which is otherwise unsubstituted in its A-ring and at positions 6, 8 and 9 except by hydrogen atoms which comprises treating the corresponding 9ot-steroid, dissolved in methanol, with sodium hydroxide.

9. A process for the preparation of a compound selected from the group consisting of a 3fi-hydroxy-5a,9fi, l0a-ll-ketoestrane, a 3B-lower alkoxy-5e,9,8,10a-1l-ketoestrane, a 3;3-hydroxy-5a,9[3,10a-11-keto-19-norpregnane and a 3,8-lower alkoxy-5a,9,6,10a-11-keto-l9-norpregnane which is otherwise unsubstituted in its A-ring and at positions 6, 8 and 9 except by hydrogen atoms which comprises treating the corresponding S a-steroid, dissolved in methanol, with sodium niethoxide.

10. A process for the preparation of a compound selected from the group consisting of a 3,6-hydroxy-5a,95, llla-ll-ketoestrane, a 3B-lower alkoxy-5a,9;8,10a-1l-ketoestrane, a 3B-hydroxy-5a,9;3,10a-11-keto-19-norpregnane and a Zip-lower alkoxy-5a,9{3,10a-11-keto-19-norpregnane which is otherwise unsubstituted in its A-ring and at positions 6, 8 and 9 except by hydrogen atoms which comprises treating the corresponding 9ec-St61'0id, dissolved in methanol, with sodium ethoxide.

11. A process for the preparation of a compound selected from the group consisting of a 3B-hydroxy-5a,9fl, 10a-11-ketoestrane, a 3,8-lower alkoxy-5a,9;3,10a-1l-ketoestrane, a 3B-hydroxy-5a,9 3,10m-11-keto-19-norpregnane and a SB-lower aikOXY-L,9[3,100-11-kiO-19-I10fp1gllfl116 which is otherwise unsubstituted in its A-ring and at positions 6, 8 and 9 except by hydrogen atoms which comprises treating the corresponding 9tx-steroid, dissolved in ethanol, with potassium hydroxide.

12. A process for the preparation of a compound selected from the group consisting of a 3;8-hydroxy-5a,9,8, 10a-11-ketoestrane, a 3fi-lower alkoxy-5a,9{3,10a-1l-ketoestrane, a 3B-hydroxy-5a,9,8,10a-11-keto-19-norpregnane and a 3fi-lower alkoxy-5a,9fi,10u-1l-keto-lQ-norpregnane which is otherwise unsubstituted in its A-ring and at positions 6, 8 and 9 except by hydrogen atoms which comprises treating the corresponding 9a-steroid, dissolved in ethanol, with sodium hydroxide.

13. A process for the preparation of a compound selected from the group consisting of a 3B-hydroxy-5u,9 9, 10a-11-ketoestrane, a 3(3-lower alkoxy-5ot,9fi,10a-ll-ketoestrane, a 3(3-hydroxy-5a,9,6,10a-1l-keto-19-norpregnane and a 3;8-lower alkoxy-5a,9,8,10u-11-keto-19-norpregnane which is otherwise unsubstituted in its A-ring and at positions 6, 8 and 9 except by hydrogen atoms which comprises treating the corresponding 9u-steroid, dissolved in ethanol, with sodium methoxide.

14. A process for the preparation of a compound selected from the group consisting of a 3fi-hydroxy-5u,9{3, 10a-11-ketoestrane, a 3B-l0wer alkoxy-5a,9[ ',10ot11-keto estrane, a 3,8-hydroxy-5a,9p,10u-11-keto-19-norpregnane and a 3,8-l0wer alkoxy-5a,9,8,10e-1l-keto-19-norpregnane which is otherwise unsubstituted in its A-ring and at positions 6, 8 and 9 except by hydrogen atoms which comprises treating the corresponding 9oz-St810id, dissolved in ethanol, with sodium ethoxide.

15. A process for the preparation of 3fl-methoxy-5a, 9,8,10a-estrane-1L17-dione which comprises treating 3pmethoxy-S a,9a,10a-estrane-1 1,17-dione, dissolved in methanol, with potassium hydroxide.

References Qited by the Examiner UNITED STATES PATENTS 3,015,666 1/1962 Farkas et al 260-3975 3,130,212 4/1964 Elks et al 260397.45

OTHER REFERENCES Burn et al.: Jour. Chem. Soc, 1957, page 4093 relied on.

Djerassi, Optical Rotation Dispersion (1960), Me- Graw-Hill, New York, page 58 relied on.

LEWIS GOTTS, Primary Examiner. 

1. A PROCESS FOR THE PREPARATION OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A 3B-HYDROXY-5A,9B,10A-11KETOESTRANE, A 3B-LOWER ALKOXY-5A,9B,10A-11-KETOESTRANE, A 3B-HYDROXY-5A,9B,10A-11-KETO-19-NORPREGNANE AND A 3B-LOWER ALKOXY-5A,9B,10A-11-KETO-19-NORPREGNANE WHICH IS OTHERWISE UNSUBSTITUTED IN ITS A-RING AND AT POSITIONS 6, 8 AND 9 EXCEPT BY HYDROGEN ATOMS WHICH COMPRISES TREATING THE CORRESPONDING 9A-STEROID WITH AN ALKALINE MEDIUM. 